Enhancing the photodynamic therapy of tumors with conjugated fluorescent quantum dot nanoparticles

Majority of anti-cancer drugs have been reported as chromophores that can transfer the energy of absorbed light to neighboring metabolites. This group of drugs has been categorized as conventional photosensitizers (PS); while the tumor therapy modality that combines the use of PS with light to generate toxic reactive oxygen species (ROS) has been termed photodynamic therapy (PDT). Moreover, recent researches and clinical studies have been reported to be currently investigating optimal combinations of PS, light sources and ligands for the efficient treatment of various cancers. On the one hand, clinical advantages of conventional PS such as the achievement of localized effects have been reported during PDT of various cancers, unlike the limited specificity of chemotherapeutic and other anti-cancer drugs. However, a number of unmet needs have also been identified in PDT based on the conventional PS agents, despite of the achieved specificity and clinical results. On the other hand, quantum dot (QD) nanocrystals have received considerable interest as PS in recent years due to improved properties such as strong absorption, durable fluorescence and cumulative yield of ROS. Indeed, the exploitation of QD unique optical properties has been the basis of their examination as PDT agents, in addition to various biological applications. Thus, this thesis addressed the improvement of tumor PDT through the development of multifunctional QD-based conjugates with tumor-specific pattern of internalization and enhanced photosensitization-mediated toxicity. Specifically, the conjugated PS complexes consisted of indium phosphide (InP) or cadmium selenide (CdSe) QDs coupled to either anticancer doxorubicin (Dox) or receptor-targeting ligands such as dopamine (DA) and Vascular Endothelial Growth Factor (VEGF). Conjugation was assessed by Electophoretic mobility shift assay (EMSA) and spectroscopic methods, whereas conjugate uptake was examined by confocal microscopy. In addition, the photosensitization-mediated toxicity was evaluated through determination of the conjugate Effective Concentration at half maximum effect (EC50) on melanoma cell lines, using Sulfo-Rhodamine B (SRB) colorimetric assays. Interestingly, QD-based PS conjugates revealed distinctive electrophoretic or spectroscopic profiles, specific uptake pattern as well as ECs50 about four to five or two times more efficient, by comparison to respective free QDs or Dox. Overall, the conjugation of QDs, to molecules that initially were or were not conventional PS, generated anti-cancer complexes that simultaneously combined efficient absorption, receptor-induced endocytosis and photosensitization-mediated toxicity, unlike conventional organic PS 1. Thus, the use of QDs, as either donors or acceptors of fluorescence resonance energy transfer (FRET) 2 within multifunctional PS conjugates, has constituted an excellent approach that would lead to the enhancement of PDT efficacy during the treatment of deep tumors, with an additional advantage of further reduced dosage of PS.

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